2023 Gruber Genetics Prize awarded for mRNA quality control

The 2023 Gruber Genetics Prize has been awarded to Dr Allan Jacobson from the University of Massachusetts and Dr Lynne Maquat from the University of Rochester, for their separate contributions to identifying and describing the mechanism of nonsense-mediated mRNA decay. This complex cellular pathway targets mRNA transcripts containing premature stop codons for degradation, thus preventing the formation of truncated, possibly toxic protein fragments.

The Genetics Prize is presented to a leading scientist, or up to three, in recognition of groundbreaking contributions to any realm of genetics research. The US$500,000 prize has been awarded every year since 2001, and was presented this week at the International Congress of Genetics in Melbourne.

Right now, millions of mRNA molecules are at work in our bodies, in a complex series of molecular dances. Mistakes are made, leading to potentially toxic proteins which can inhibit the normal functioning of cells and normal human development.

The body’s quality control of this process was identified by Maquat and Jacobson in the 1980s and 90s, when they showed how our cells destroy faulty mRNA molecules. They demonstrated that mRNA is much more than a passive carrier of genetic code; it plays a central role in gene regulation. They named this quality control process nonsense-mediated mRNA decay (NMD).

Through his yeast genetic studies, Jacobson identified the core components of the NMD pathway, demonstrating the role that UPF proteins play in targeting mRNAs with a premature stop codon for degradation. He was also able to demonstrate the role this pathway plays as a quality control checkpoint for mRNAs with a premature stop codon, whether due to a mutation or gene expression errors.

Through her studies of patients with haemolytic diseases, Maquat demonstrated the importance of NMD in humans, by showing that mRNAs with a premature stop codon were more unstable. She went on to elucidate NMD mechanisms in mammalian cells and also showed that NMD acts to eliminate faulty transcripts that are the by-product of routine errors in human gene expression, and that cells use NMD to adapt to changes in the environment, through the fine-tuning of 5–10% of mRNAs.

Working independently, the two researchers have changed our understanding of the role that mRNA regulation plays in ensuring the proper workings of a cell, showing that NMD acts as a mechanism by which a cell can respond to environmental changes. These days, Maquat’s lab is investigating the role of NMD in Fragile X syndrome — the most common single gene cause of intellectual disability and autism — while Jacobson founded a company that is now trialling treatments for Duchenne muscular dystrophy (DMD).

“Through their creativity and dedication to fundamental discovery research, Maquat and Jacobson have elucidated a crucial post-transcriptional regulatory pathway that eliminates transcripts containing a premature stop codon,” said Professor Philip Hieter, a member of the Selection Advisory Board to the Prize. “Their discoveries of the molecular components and mechanism of nonsense-mediated mRNA decay have been paradigm-shifting, in our understanding of how cells avoid expression of potentially deleterious mRNA transcripts and in the genetics of human disease.”

“As the best characterised and most highly conserved RNA quality control mechanism, understanding NMD opened scientists’ eyes to a new level of genetic regulation that reviews normal as well as mutated mRNAs and provides cells with previously unappreciated resilience and adaptability,” added Professor Allan Spradling, Chair of the Selection Advisory Board. “Already these insights have profound implications in treating human diseases, and the importance of this topic will continue to grow rapidly in the years to come.”

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